Visit our Expo - Redox and Inflammation signaling 2012

Session II : Receptor signaling and G proteins Poster II, 40
Oxytocin- and vasopressin-induced mitogenic signalling in human small-cell lung
carcinoma
Christel Péqueux1, Marie-Thèrèse Hagelstein2, Jean-Claude Hendrick2 and Jean-
Jacques Legros2.
1Tumour and Development Biology Laboratory, CRCE, Pathology Institute, CHU-B23,
University of Liège, B-4000 Liège, Belgium, e-mail: C.Pequeux@ulg.ac.be;
2Neuroendocrine unit, CIL, Pathology Institute, CHU-B23, University of Liège, B-4000
Liège, Belgium, e-mail: Jean-Jacques.Legros@ulg.ac.be
Neuroendocrine tumour cells usually develop very potent autocrine/paracrine signalling
pathways that play a crucial part in the dysregulation of cellular growth. In the study
presented here, we demonstrated, on small cell lung carcinoma (SCLC) cell lines, that the
oxytocin (OT) as well as the vasopressin (VP) genes, normally transcriptionally restricted in
their expression, are activated in SCLC, leading to synthesis and secretion of OT and VP.
Concomitantly, these tumour cells express the various neuropeptide receptors: OTR, V1aR,
V1bR/V3R and V2R. We observed that OT, as well as VP, induces a dose dependent and
time persistent increase of tumour cell proliferation. This mitogenic effect of OT was
completely abolished by the OTR antagonist OVTA. We demonstrated that OT- and VPinduced
mitogenic effects on SCLC are largely mediated by the OTR and the V1aR
respectively and that this mitogenic signalling passes through the phosphorylation of ERK1/2
and p90RSK in a PLC-, Ca++-, PKC- and MEK1/2-dependent pathway. Moreover, we
evidenced that growth of OT- and VP-stimulated SCLC could be down regulated by
signalling inhibitors and was not a consequence of toxicity. Additionally, we reported that
86% of primary SCLC biopsies analyzed expressed at least the OTR and that 71% expressed
the OTR, the V1aR and the V2R altogether. Interestingly, in normal human lung, OTR
colocalized with vascular endothelial cells of the lung. Among SCLC plasma samples, the
distribution of elevated OT is 40%, of elevated VP is 43.3% and of both elevated hormones is
16.7%. Altogether, these results clearly demonstrate that, in addition to the vasopressinergic
system, OT and particularly OTR contribute to give the SCLC tumour a survival advantage.
Our data identify pathways by which OT and VP induced their mitogenic action on SCLC and
they highlight that blocking of their receptor signalling represents viable pharmacological
targets.
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